RGS12 Is a Novel Critical NF-κB Activator in Inflammatory Arthritis
Gongsheng Yuan,
Shuting Yang,
Andrew Ng,
Chuanyun Fu,
Merry Jo Oursler,
Lianping Xing,
Shuying Yang
Affiliations
Gongsheng Yuan
Department of Basic and Translational Sciences, School of Dental Medicine, University of Pennsylvania, Philadelphia, PA, USA
Shuting Yang
Department of Basic and Translational Sciences, School of Dental Medicine, University of Pennsylvania, Philadelphia, PA, USA
Andrew Ng
Department of Oral Biology, School of Dental Medicine, University of Buffalo, State University of New York, Buffalo, NY, USA
Chuanyun Fu
Department of Basic and Translational Sciences, School of Dental Medicine, University of Pennsylvania, Philadelphia, PA, USA
Merry Jo Oursler
Department of Medicine, Endocrine Research Unit, Mayo Clinic, Rochester, MN, USA
Lianping Xing
Department of Pathology and Laboratory Medicine, Center for Musculoskeletal Research, University of Rochester Medical Center, Rochester, NY, USA
Shuying Yang
Department of Basic and Translational Sciences, School of Dental Medicine, University of Pennsylvania, Philadelphia, PA, USA; The Penn Center for Musculoskeletal Disorders, School of Medicine, University of Pennsylvania, Philadelphia, PA, USA; Center for Innovation & Precision Dentistry, School of Dental Medicine, School of Engineering and Applied Sciences, University of Pennsylvania, Philadelphia, PA, USA; Corresponding author
Summary: Rheumatoid arthritis (RA) is the most common inflammatory disease, which currently lacks effective treatment. Here, we discovered that the Regulator of G Protein Signaling 12 (RGS12) plays a key role in regulating inflammation. Transcriptional and protein analysis revealed that RGS12 was upregulated in human and mouse RA macrophages. Deletion of RGS12 in myeloid lineage or globally inhibits the development of collagen-induced arthritis including joint swelling and bone destruction. Mechanistically, RGS12 associates with NF-κB(p65) to activate its phosphorylation and nuclear translocation through PTB domain, and NF-κB(p65) regulates RGS12 expression in a transcriptional manner. The nuclear translocation ability of NF-κB(p65) and RGS12 can both be enhanced by cyclooxygenase-2 (COX2). Furthermore, ablation of RGS12 via RNA interference significantly blocks the inflammatory process in vivo and in vitro. These results demonstrate that RGS12 plays a critical role in the pathogenesis of inflammatory arthritis.
